title: COX10 mutations resulting in complex multisystem mitochondrial disease that remains stable into adulthood.
abstract: OBJECTIVE
  Isolated cytochrome-c oxidase (COX) deficiency is one of the most frequent respiratory chain defects seen in human mitochondrial disease. Typically, patients present with severe neonatal multisystem disease and have an early fatal outcome. We describe an adult patient with isolated COX deficiency associated with a relatively mild clinical phenotype comprising myopathy; demyelinating neuropathy; premature ovarian failure; short stature; hearing loss; pigmentary maculopathy; and renal tubular dysfunction.
  
  
  METHODS
  Whole-exome sequencing detected 1 known pathogenic and 1 novel COX10 mutation: c.1007A>T; p.Asp336Val, previously associated with fatal infantile COX deficiency, and c.1015C>T; p.Arg339Trp. Muscle COX holoenzyme and subassemblies were undetectable on immunoblots of blue-native gels, whereas denaturing gels and immunocytochemistry showed reduced core subunit MTCO1. Heme absorption spectra revealed low heme aa3 compatible with heme A:farnesyltransferase deficiency due to COX10 dysfunction. Both mutations demonstrated respiratory deficiency in yeast, confirming pathogenicity. A COX10 protein model was used to predict the structural consequences of the novel Arg339Trp and all previously reported substitutions.
  
  
  CONCLUSIONS
  These findings establish that COX10 mutations cause adult mitochondrial disease. Nuclear modifiers, epigenetic phenomenon, and/or environmental factors may influence the disease phenotype caused by reduced COX activity and contribute to the variable clinical severity related to COX10 dysfunction.
authors.affiliation: Medical Research Council Centre for Neuromuscular Diseases, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, England.
authors.forename: Robert D S
authors.initials: RD
authors.lastname: Pitceathly
authors.affiliation: Department of Clinical Neuroscience, University College London Institute of Neurology, London, England.
authors.forename: Jan-Willem
authors.initials: JW
authors.lastname: Taanman
authors.affiliation: Medical Research Council Centre for Neuromuscular Diseases, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, England3Mitochondrial Research Group, Clinical and Molecular Genetics Unit, Universi.
authors.forename: Shamima
authors.initials: S
authors.lastname: Rahman
authors.affiliation: Centre de Génétique Moléculaire, UPR3404, Centre national de la recherche scientifique, Gif-sur-Yvette, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Meunier
authors.affiliation: Division of Mathematical Biology, National Institute for Medical Research, London, England.
authors.forename: Michael
authors.initials: M
authors.lastname: Sadowski
authors.affiliation: Dubowitz Neuromuscular Centre, University College London Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London, England.
authors.forename: Sebahattin
authors.initials: S
authors.lastname: Cirak
authors.affiliation: Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, England.
authors.forename: Iain
authors.initials: I
authors.lastname: Hargreaves
authors.affiliation: Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, England.
authors.forename: John M
authors.initials: JM
authors.lastname: Land
authors.affiliation: Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, England.
authors.forename: Tina
authors.initials: T
authors.lastname: Nanji
authors.affiliation: Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, England.
authors.forename: James M
authors.initials: JM
authors.lastname: Polke
authors.affiliation: Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, England.
authors.forename: Cathy E
authors.initials: CE
authors.lastname: Woodward
authors.affiliation: Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, England.
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sweeney
authors.affiliation: Department of Clinical Neuroscience, University College London Institute of Neurology, London, England.
authors.forename: Shyam
authors.initials: S
authors.lastname: Solanki
authors.affiliation: Dubowitz Neuromuscular Centre, University College London Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London, England.
authors.forename: A Reghan
authors.initials: AR
authors.lastname: Foley
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, England.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, England.
authors.forename: Jim
authors.initials: J
authors.lastname: Stalker
authors.affiliation: Department of Clinical Neurophysiology, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, England11Department of Clinical Neurophysiology, Norfolk and Norwich University Hospital, Norwich, Engla.
authors.forename: Julian
authors.initials: J
authors.lastname: Blake
authors.affiliation: Medical Research Council Centre for Neuromuscular Diseases, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, England12Division of Neuropathology, University College London Institute of Neurolog.
authors.forename: Janice L
authors.initials: JL
authors.lastname: Holton
authors.affiliation: Dubowitz Neuromuscular Centre, University College London Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London, England12Division of Neuropathology, University College London Institute of Neurology, London, E.
authors.forename: Rahul
authors.initials: R
authors.lastname: Phadke
authors.affiliation: Dubowitz Neuromuscular Centre, University College London Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London, England.
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.affiliation: Medical Research Council Centre for Neuromuscular Diseases, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, England13Department of Molecular Neuroscience, University College London Institute o.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
authors.affiliation: Medical Research Council Centre for Neuromuscular Diseases, University College London Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, England13Department of Molecular Neuroscience, University College London Institute o.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hanna
mesh_terms: D000328:Adult; D019883:Alkyl and Aryl Transferases / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics*; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008565:Membrane Proteins / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics*; D013497:Sural Nerve / Q000473:pathology / Q000648:ultrastructure; D015003:Yeasts / Q000235:genetics
chemical_list: D008565:Membrane Proteins; C490115:COX10 protein, human; D003576:Electron Transport Complex IV; D019883:Alkyl and Aryl Transferases